Waardenburg syndrome

Definition

Waardenburg syndrome (WS) encompasses several different hereditary disorders, the main features of which variably include abnormal pigmentation, hearing loss, and a subtle difference in facial features. Certain other physical anomalies occur less frequently in WS.

Description

In 1951, Dr. Petrus Waardenburg reported a syndrome of dystopia canthorum, heterochromia of the irides, and hearing loss. Dystopia canthorum (also called telecanthus) describes a subtle but unusual facial feature in which the inner corners of the eyes (canthi) are spaced farther apart than normal, yet the eyes (pupils) themselves are normally spaced. The result is that the eyes appear to be widely spaced, even though they are not. Heterochromia means different-colored, and irides is the plural form of iris-;the colored portion of the eye. Thus, someone with heterochromia of the irides has differentcolored eyes, often one brown and one blue. Another feature not originally noted by Dr. Waardenburg, but now considered a major sign of WS is a white forelock (white patch of hair extending back from the front of the scalp). In fact, disturbances in pigmentation (coloring) of various parts of the body are consistent features of WS. Uncommon but serious physical anomalies associated with WS include Hirschprung disease (intestinal malformation), spina bifida, cleft lip/palate, and musculoskeletal abnormalities of the arms.

Five types of WS have been defined based on clinical symptoms or genetic linkage. As of 2000, six different genes were associated with WS. Most families show autosomal dominant inheritance, but autosomal recessive inheritance and sporadic (single) cases are also seen. People with WS are not at increased risk for mental retardation, and vision loss is not more common. For the majority of those with WS, hearing loss is the only major medical problem they will have.

WS1 is the "classic" form of WS, and if someone uses just the name Waardenburg syndrome (with no modifying number), they are most likely referring to the group of disorders as a whole or just WS1. WS2 may occasionally be referred to as WS without dystopia canthorum. WS3 is also known as Klein-Waardenburg syndrome, as well as WS with upper limb anomalies. Alternate names for WS4 include Waardenburg-Hirschprung disease, Waardenburg-Shah syndrome, Shah-Waardenburg syndrome, and Hirschprung disease with pigmentary anomaly.

Genetic profile

Since Dr. Waardenburg's original description of his patients in 1951, many more families with the same or similar symptoms have been reported. By 1971, it became clear that a proportion of families have WS without dystopia canthorum. At that point, Waardenburg syndrome was divided into two distinct types, WS1 and WS2. In addition, a few individuals with typical signs of WS1 were found to also have musculoskeletal symptoms. This form of the disorder was named Klein-Waardenburg syndrome, now also known as WS3. Further, some researchers noted yet a different pattern of anomalies involving pigmentation defects and Hirschprung disease, which eventually became known as WS4. Finally, genetic testing of WS2 families has shown at least two subtypes-;those that show genetic linkage are designated as WS2A and WS2B.

The four major types of WS have all been studied through DNA (genetic) analysis. There is some agreement between the clinical subtypes of WS and mutations in different genes, but genetic analysis has also served to confuse the naming scheme somewhat. The different types of WS, their inheritance patterns, and the genes associated with them, are listed below.

WS1

A number of different mutations in a single copy of the PAX3 gene on chromosome 2 are responsible for all cases of WS1, meaning it is always inherited as an autosomal dominant trait. The PAX3 gene plays a role in regulating other genes that have some function in producing melanocytes (pigment-producing cells). PAX3 was formerly known as the HUP2 gene.

WS2A

People who have typical signs of WS2 are designated as having WS2A only if genetic testing shows them to have a mutation in the MITF gene on chromosome 3. As with WS1, all cases of WS2A appear to be autosomal dominant. There is evidence that MITF is one of the genes regulated by PAX3.

WS2B

Some individuals with typical WS2 have had normal MITF gene analysis. A search for a different WS2 gene showed that some cases are linked to a gene on chromosome 1. This gene has been tentatively designated WS2B until its exact chromosomal location and protein product are identified. WS2B displays autosomal dominant inheritance.

WS3

Several people with a severe form of WS1 have been shown by genetic analysis to have a deletion of a small section of chromosome 2. Several genes are located in this section, including the PAX3 gene. Not all patients with WS3 have had the exact same genetic anomaly on chromosome 2, which may explain the variation in symptoms that have been reported. Some families with WS3 have displayed autosomal dominant inheritance, while other individuals with the condition have been sporadic cases.

Source: http://health.families.com/waardenburg-syndrome-1183-1187-gecd